Hepatic insulin resistance (HIRE) is a significant clinical hallmark of type 2 diabetes (T2D) that results in impaired insulin signaling, increased gluconeogenesis, hyperlipidemia, and progressive nonalcoholic fatty liver disease (NAFLD). Despite active investigation, therapeutic strategies are limited and there is much elucidation needed to determine the specific etiological molecules responsible for HIRE, T2D, and NAFLD. PANcreatic-Derived factor (PANDER) is a recently discovered protein that is regulated by glucose and highly expressed and secreted from the endocrine pancreas. My laboratory and others have demonstrated a physiological role for PANDER in glycemic regulation via interaction with both the liver and pancreas. Our PANDER transgenic (PANTG) pancreas-specific mouse that has increased circulating levels of PANDER has revealed a phenotype containing several T2D characteristics such as fasting hyperglycemia, glucose intolerance, hepatic insulin resistance and increased hepatic triglyceride production. However, the precise PANDER induced hepatic signaling mechanisms are unknown along with levels of circulating PANDER in physiological and pathophysiological states. The objective of this application is to elucidate the PANDER induced hepatic lipogenic signaling mechanism and reveal that circulating PANDER levels are increased during insulin resistance. Preliminary data employing proteomic analysis of this PANTG model revealed lipid metabolism as a significantly impacted cellular function across metabolic states with approximately 50 differentially expressed proteins involved with this function. The top canonical mechanism impacted in both the fed and fasted state within the PANTG was the liver X receptor (LXR) pathway. Therefore, our central hypothesis is that hyperglycemic conditions will result in increased systemic levels of PANDER promoting hepatic lipogenesis via activation of the liver X receptor pathway. To address this hypothesis, we propose three specific aims: (1) Determine the PANDER induced hepatic signaling molecules by examining the proteomic and transcriptional profile of the PANKO model and primary hepatocytes, (2) Elucidate the effect of PANDER on liver X receptor (LXR) expression and activity, and (3) Measure the physiological and pathophysiological levels of circulating PANDER in T2D murine models and human subjects. To accomplish these specific aims, we are utilizing state of the art proteomic technology in combination with the only established PANDER animal models available for analysis of this unique secreted protein. Our approach will potentially identify a novel molecule, mechanism, biomarker and putative etiological agent of HIRE, T2D, and NAFLD.